PROJECT SUMMARY Previously lethal, critical congenital heart disease (CHD) can now be treated effectively with surgical, catheter, and medical interventions. The resulting dramatic improvement in life expectancy has brought a major demographic shift, so that adult patients with CHD now outnumber children with CHD, even for complex conditions. Adult survivors are at increased risk of anxiety, depression, social difficulties, lower educational attainment, and underemployment. These psychosocial morbidities may be associated with deficits in executive functions (EFs) and other neurocognitive abilities that are prevalent in children and adolescents with CHD. Deficits in EFs, represented by measures of inhibitory control, working memory, cognitive flexibility, and decision-making, are highly dependent on the integrity of cortical and subcortical neural networks that continue to develop into early adulthood and can have a major adverse impact on self-regulation and management. The goal of our proposal is to bridge the gap in knowledge between known executive function deficits in childhood CHD and adult well-being. We propose to accomplish our goal by studying subjects, now age 24-28 years, who were enrolled as infants in the Boston Circulatory Arrest Study and then studied with respect to neurolopsychological and developmental function at ages 1, 2.5, 4, 8, and 16 years, as well as with brain MRI at 16 years. In Aim 1, we will explore the relationship of EFs to major dimensions of adult well-being. We hypothesize that lower performance on EFs will be related to poorer overall well-being. The outcomes measured to determine well-being will be quality of life, neuropsychological function (e.g. social cognition, memory skills), mental health diagnosis and function (e.g. anxiety, depression), social relatedness, academic achievement, and adult independence (e.g. employment status, medical follow up). In Aim 2, we will determine the relationship of EFs to MRI-derived measures of brain structure, function, and connectivity. We hypothesize that lower performance on EFs will be associated with lower global efficiency (integration) and higher modularity (segregation). We will measure the brain MRI outcomes using global white matter connectivity, regional cortical gray matter thickness, gray matter connectivity measured from interregional correlation in cortical thickness, and functional connectivity as defined by resting state functional magnetic resonance imaging. In Aim 3, we will use longitudinal models to analyze the association of adult well-being with earlier measures of EFs and other neurocognitive and mental health variables, as well as with earlier clinical variables and adolescent neuroimaging. We will analyze associations of adult well-being dimensions with childhood and adolescent EFs, other measures of mental health and cognitive function, adolescent brain MRI findings, and clinical variables. Our ultimate goal is to identify early, modifiable risk factors for adult performance to guide the design of targeted treatment strategies that optimize educational achievement, employability, and quality of life in the burgeoning population of adults with CHD.